16-aminomethylene-17-oxo steroids and preparation thereof



United States Patent 3,030,357 16-AMlNOMETHYLENE-17-0X0 STEROIDS AND PREPARATION THEREOF Raymond 0. Clinton, East Greenbush, N.Y., assignor to Sterling Drug Inc., New York, N.Y., a corporation of Delaware No Drawing. Filed Jan. 29, 1960, Ser. No. 5,343

30 Claims. (Cl. 260-4395) erties, is well known. Such steroid moietie have from seventeen to about twenty-three carbon atoms, not counting carbon content which may be provided by esterified hydroxy groups. Esterified hydroxy-steroids are included within the scope of the invention, but the carbon content contributed by the acid moiety of the ester is not considered part of the essential carbon content of the steroid.

The steroid moiety can be any member of the estrane, androstane or etiocholane series. The foregoing can contain varying degrees of unsaturation and a variety of substituents in the form of hydrocarbon radicals or functional groups conventionally employed in the steroid art. The steroid moiety can have one or more substituents at various positions of the nucleus, for example, hydroxy, mercapto, acyloxy or oxo radicals at positions 1, 2, 3, 4, 5, 6, 7, 11, 12 or 14; halogen atoms, preferably fluorine, chlorine or bromine, for example, at the 2-, 4-, 6-, 7-, 9- or 12-positions; epoxy bridges, for example, at the 4,5-, 5,6- or 9,1l-positions, and lower-alkyl groups, for example, at the 1-, 2-, 3-, 4-, 6-, 7- or ll-positions. The steroid moiety can also have one or more double bonds, especially at the 1,2-, 4,,5-, 5,6-, 6,7- or 9,1l-positions, and compounds where ring A or both rings A and B are aromatic are also contemplated. The steroid moiety usually possesses angular methyl groups at C and C although 18- and 19-nor-steroids and 18,19- bisnor-steroids lacking one or both of the angular methyl groups at C and C respectively, are also contemplated.

The 18,19-bisnor-steroid, 18- or l9-nor-steroid, and normal steroid moieties in the compounds of the invention contain respectively, seventeen, eighteen and nineteen carbon atoms plus any carbon content which may be provided by one or more nuclearly substituted hydrocarbon radicals, up to and including a total of about twentythree carbon atoms.

When acyloxy radicals are present in the steroid moiety, the acyl radicals are preferably derived from carboxylic acids having from one to about ten carbon atoms, conventionally employed in the steroid art, and having a molecular weight less than about 200. Representative of the acyl radicals which can be present are lower-alkanoyl radicals, e.g,, formyl, acetyl, propionyl, butyryl, isobutyryl, caproyl, heptanoyl, octanoyl, trimethylacetyl, and the like; carboxy-lower-alkanoyl radicals, e.g., succinyl (fi-carboxypropionyl); cycloalkyl-lower-alkanoyl radicals, e.g., B-cyclopentylpropionyl, B-cyclohexylpropionyl, and the like; monocarbocyclic aroyl radicals, e.g., benzoyl, p-toluyl, p-nitrobenzoyl, 3,4,5-trimethoxybenzoyl, and the like; .monocarbocyclic aryl-lower-alkanoyl or -alkenoyl radicals, such as phenylacetyl, B- henylpropionyl, cinnamoyl, and the like; and monocarbocyclic aryloxy-loweralkanoyl radicals; such as p-chlorophenoxyacetyl, and the like. Esters of inorganic acids such as phosphoric acid are also contemplated.

In the l6-(l-aminoalkylidene) substituent, =C(R)- N=B, the portion N=B stands for primary amino (H N) or a basic secondary or tertiary amino radical having a molecular weight less than about 200. By a secondary amino radical is meant a radical of the type YHN- wherein Y is an organic substituent so that the complete molecule to which it is attached is a secondary amine. By a tertiary amino radical is meant a radical of the type YYN wherein Y and Y are both organic substituents so that the complete molecule to which it is attached is a tertiary amine. Basic amino radicals are those of the aliphatic or araliphatic type that impart to the molecules which contain them sufiicient basicity so that the compounds readily form acid-addition salts with strong inorganic and organic acids. -A particularly preferred group of amino radicals are primary amino (H N); lower-alkylamino, for example, methylamino and ethylamino; cycloalkylamino in which the cycloalkyl has from 3 to 7 ring members, for example, cyclopropylamino, cyclopentylamino, cyclohexylamino and cycloh-eptylamino; phenyl-lower-alkylamino, for example, benzylamino and phenylethylamino; di-lower-alkylamino, for example, dimethylamino and diethylamino; dicycloalkylamino in which cycloalkyl has from 3 to 7 ring members, for example, dicyclopentylamino' and dicyclohexylamino; N-(cycloalkyl)-lower-alkylamino in which the cycloalkyl has from 3 to 7 ring members, for example, N-methylcyclohexylamino and N-ethylcyclopentylamino; polymethylenimino having from 5 to 7 ring members, for example, l-pyrrolidyl, l-piperidyl, hexamethylenimino and lower-alkylated derivatives thereof; 4-morpholinyl; di- (phenyl-lower-alkyl)amino, for example, dibenzylamino and bis(phenylethyl)amino; N- (phenyl-lower-alkyl)- lower-alkylamino, for example, N-benzylmethylamino; di-lower-alkylamino-lower-alkylamino,-for example, dimethylaminoethylamino; and polymethylenimino-loweralkylamino, for example, l-piperidylethylamino. In the foregoing radicals, the term .lower-alkyl stands for alkyl groups containing from one to about six carbon atoms with the additional proviso that in the di-lower-alkylamino-lower-alkylamino and polymethylenimino-loweralkylamino radicals, the two nitrogens are separated by at least two carbon atoms.

The compounds of the invention are prepared by reacting a 16-(l-hydroxyalkylidene)-17-oxo-steroid with ammonia or a basic amine, HN=B, according to the following equation:

wherein Q represents the remaining portion of the steroid moiety described above. The condensation takes place by heating the 16-(l-hydroxyalkylidene)-17-oxo-steroid with at least one molar equivalent of HN=B in an inert solvent or reaction medium at a temperature between about 50 C. and C. The nature of the inert solvent is not critical, although hydrocarbon solvents such as benzene, toluene or xylene, or lower-alkanols, e.g., ethanol are preferred. 7

A particularly preferred group of compounds comprises 16-(l-aminoalkylidene)-17-oxo-steroids of the androstane or etiocholane series, in which the steroid moiety has from seventeen to about twenty-three carbon 4 wherein R represents hydrogen or lower-alkyl; R

atoms exclusive of ester radicals, including those having the structural formula represents hydrogen or carboxylic acyl; X represents H (H) (OH) or O; Y and Y represent hydrogen or methyl, and N=B represents unsubstituted amino, or secondary or tertiary amino having a molecular weight less than about 200. Also vcontemplated are the corresponding compounds having a double bond in the 5,6-position:

Another particularly preferred group of compounds comprises 16-(l-aminoalkylidene)-17-oxo-steroids of the estrane series, in which the steroid moiety has from seventeen to about nineteen carbon atoms exclusive of ester radicals, including those having the structural formula 0 Y I x=l GN=B III wherein R, X, Y and N=B have the same meanings as given above, and R represents hydrogen, lower-alkyl or carboxylic acyl.

Still another particularly preferred group of compounds comprises 2,16-bis( l-aminoalkylidene)-3,17-dioxo-steroids in which the steroid moiety has from seventeen to about twenty-one carbon atoms exclusive of ester radicals including those having the structural formula wherein R, X, Y, Y and N=B have the same meanings as given above, including the corresponding compounds having adouble bond in the 4,5 -position:

The compounds of Formulas I, II and III are prepared by reacting the appropriate 16-(1-hydroxyalkylidene)-l7- oxo-steroid, viz.:

VII

R, X, Y and Y having the same meanings given above. The corresponding A -unsaturated compounds lead to compounds of Formula V.

16-(l-aminoalkylidene)-17-oxo-steroids having a 3-oxo substituent, viz.:

and the corresponding M-unsaturatecl compounds, wherein R, R, X, Y, Y and N=B have the same meanings given hereinabove, are also within the scope of the invention but cannot be prepared directly from the parent 3,17-dioxo-steroid because of the reactivity of the 3-oxo substituent. Compounds of Formula IX can, however, be synthesized as follows. A compound of Formula I or H where R represents hydrogen is oxidized by means of reagents conventionally used to oxidize carbocyclic hydroxy groups to oxo groups, e.g., chromic oxide or the reagents of the Oppenauer procedure (a volatile ketone and the aluminum salt of an organic hydroxy com pound).

Alternatively, one can start with a steroid of the type:

group then oxidized under non-acidic conditions as by chromic oxide in pyridine. The resulting 17-oxo-3-ketal, as illustrated by the structure GH -o Urn-o is then subjected to the reactions previously described to introduce a hydroxyalkylidene group in the l6-position. The resulting compound is reacted with an amine, HN B, and the ketal is finally cleaved with dilute acid to give a compound of Formula IX. An oxo group at the ll-position (X O) is relatively unreactive and need not be protected before introduction of the hydroxyalkylidene group or reaction with an amine.

The intermediate 16-hydroxyalkylidene-l7 oxo-steroids (I) are prepared by condensing the appropriate 17-oxosteroid with a lower-alkyl lower alkanoate, RCOOR, wherein R represents hydrogen or lower-alkyl and R" represents lower-alkyl, in the presence of a strong base under anhydrous conditions. The strong base is preferably an alkali metal lower-alkoxide, amide or hydride. An acyl group enters the 16-position with elimination of a molecule of an alcohol as follows:

The 16-acyl steroid in solution is in tautomeric equilibrium with its enol form (hydroxyalkylidene, =C(R)-OH) and the latter form is the one chosen for convenience in the structural formulas given elsewhere in this specification.

In the case wherein the radical R represents lower-alkyl an alternative and preferred method comprises treating the 17-oxo-steroid with a lower-alkanoic acid anhydride in the presence of boron trifluoride.

In the event that the starting material contains a 3-oxo radical as well as a l7-oxo radical, the hydroxyalkylidene group also enters the 2-position to give a 2,16- bis( l-hydroxyalkylidene) -3 l7-dioxo-steroid, exemplified by Formula VIII above, intermediates for the 2,16-bis- (aminoalkylidene) compounds of Formula IV.

The intermediate steriods and 2,l6-bis(l-hydroxyalkylidene)-3,l7-dioxosteroids are disclosed in my copending application, Serial No. 835,434, filed August 24, 1959.

The compounds of the invention are basic in character and will form acid-addition salts upon addition of strong acids. Those compounds which are tertiary-amines will also form quaternary ammonium salts upon addition of esters of strong acids. These salts are the full equivalent of the corresponding free bases insofar as their physiological properties are concerned. Both the free base and salt forms are considered to be one and the same invention.

The acid-addition salts are prepared by causing the 16-( l-aminoalkylidene) -steroid to react with a strong inorganic or organic acid, usually in an inert solvent or reaction medium. Examples of appropriate acids include hydrochloric, hydrobromic, sulfuric, phosphoric, citric, tartaric, quinic, benzenesulfonic acid, and the like.

The quaternary ammonium salts of the compounds of the invention are prepared by causing a l6-(1-tertiaryaminoalkylidene)-steroid to react with an ester of a strong inorganic or organic sulfonic acid, said ester preferably having a molecular weight less than about 20 0. A particularly preferred class of esters, because of their ready availability, are lower-alkyl, lower-alkenyl and monocarbocyclic aryl-lower-alkyl esters, for example, methyl iodide, ethyl iodide, ethyl bromide, propyl bromide, butyl bromide, allyl bromide, methyl sulfate, methyl benzenesulfonate, methyl p-toluenesulfonate, benzyl chloride, o-chlorobenzyl chloride, and the like. The reaction of the 16-(1-tertiary-aminoalkylidene) -steroid and the quaternizing agent takes place upon simple admixture of the components, preferably in the presence of an inert organic solvent, although heating may be applied to accelerate the reaction.

The acid-addition and quaternary ammonium salts preferably have anions which are pharmacologically acceptable, that is, the anions do not appreciably increase the toxicity of the compound as a whole toward animal organisms. Such anions include, for example, the chloride, bromide, iodide, sulfate or acid sulfate, methanesulfonate, benzenesulfonate, and the like. Salts having toxic anions are, however, useful in that they serve as characterizing derivatives of the l6-(1-aminoalkylidene)- steroid, and serve as intermediates for non-toxic quaternary salts by conventional ion exchange reactions. All acid-addition salts, regardless of the nature of the anions, are useful as intermediates in the purification of the free bases.

Endocrinological studies of the compounds of the invention have shown that they possess useful metabolic, hormonal and anti-hormonal properties. In particular, they exhibit pituitary inhibiting activity. Pituitary inhibiting agents are useful in the treatment of endocrinological disorders brought about by hormonal imbalance.

Pharmacological evalution has demonstrated that compounds of the invention also possess hypotensive properties thus indicating their usefulness in lowering blood pressure.

The compounds of the invention can be prepared for use by dispersing them in an aqueous suspension or by dissolving them in a pharmacologically acceptable oil or oil-Water emulsion for parenteral administration; or by incorporation in tablet form with excipients for oral administration.

The structure of the compounds of the invention was established by the mode of synthesis, their ultraviolet and infrared spectra, and by the fact that the values found upon elementary analysis corresponded with the values calculated for the assigned structures.

The following examples will further illustrate vthe invention without the latter being limited thereby.

Example 1 l6 [(l-piperidyl)methylene]androstan 35 ol 17- one [1; R is H, R is H, X is H Y and Y' are CH N=B is N(CH A mixture of 1.59 g. of 16-hydroxymethyleneandrostan-3/3-oll7-one, 0.6 ml. of piperidine and 40 ml. of benzene was refluxed for two hours in a Bidwell-Sterling moisture trap apparatus to collect the water formed in the reaction. The reaction mixture was concentrated in vacuo, and the residue was triturated with ether, giving 1.89 g. of crystalline product, M.P. 197-499 C. (uncorr.). Recrystallization of the latter from benzene and N=B is NH(CH CH can be prepared by 7 from an ethyl acetate-ether mixture, and drying at 50 C. for nine hours in vacuo, gave l6-[(l-piperidyl)methylene]androstan-3/8-ol-l7-one in the form of pale yellow prisms, MP. l99.5202.7 C. (corn), [a] =-|-63.4 i-0.5 (1% in chloroform); ultraviolet maximum at 320 m (E=25,700)

Analysis.-Calcd. for C H NO C, 77.86; H, 10.20; N, 3.63. Found: C, 77.92; H, 10.08; N, 3.64.

In many cases where the reaction between the steroid and amine is relatively rapid, the use of a water separator is not necessary. The reaction can be carried to completion by distilling or boiling off the benzene reaction mixture which removes azeotropically the water formed in the reaction.

16 [(1 piperidyl)methylene] androstan 35 ol 17- one reacts with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, tartaric acid, quinic acid, naphthalenesulfonic acid, methyl iodide, ethyl bromide, allyl bromide, benzyl chloride, or 2-chlorobenzyl chloride to give the hydrochloride, hydrobromide, sulfate (or bisulfate), phosphate (or acid phosphate), tartrate (or bitartrate), quinate, naphthalenesulfonate, methiodide, ethobromide, allobromide, benzochloride, or 2-chlorobenzochloride salts, respectively.

16 l piperidyl)methylene] androstan 36 o1 17- one can be reacted with acetic anhydride, propionic anhydride, caproyl chloride, succinic anhydride, B-cyclopentylpropionyl chloride, benzoyl chloride, p-nitrobenzoyl chloride, 3,4,5-trimethoxybenzoyl chloride, phenylacetyl chloride, or cinnarnoyl chloride, by heating in the presence of pyridine, to give, respectively, 3fi-acetoxy-l6-[(lpiperidyl)methylene]androstan 17 one, 313 propionoxy 16 [(1 piperidyl)methylene]androstan 17- one, 313 caproyloxy 16 [(1 piperidyl)methylene]- androstan 17 one, 3 3 (B carboxypropionoxy) 16- [(1 piperidyl)methylene]androstan l7 one, 38 (B- cyclopentylpropionoxy) 1'6 [(1 piperidyl)methylene]- androstan 17 one, 3 3 benzoyloxy 16 [(1 piperidyl)methylene]androstan 17 one, 3,8 (p nitrobenzoyloxy) 16 [(1 piperidyl)methylene]androstan 17- one, 318 (3,4,5 trimethoxybenzoyloxy) 16 [(1- piperidyl)methylene]androstan 17 one, 3,8 phenylacetoxy 16 [(1 piperidyl)methyleneJandrostan 17- one, or 3B cinnamoyloxy 16 [(1 piperidyl)methylene]-androstan-l7-one.

Example 2 16 [(n hexyl)aminomethyleneJandrostan 35 ol- 17-one [I; R is H, R is H, X is H Y and Y are CH replacing the piperidine in Example 1 by a molar equivalent amount of n-hexylamine.

piperidine in Example 1 by a molar equivalent amount of benzylamine.

Example 5 16 (cyclopropylaminomethylene)androstan 3p ol- 17-one'[I; R is H, R is H, X is H Y and Y are CH N=B is NHCH(CH3)2] can be prepared by replacing the piperidine in Example 1 by a molar equivalent amount of cyclopropylamine.

Example 6 16 (cycloheptylaminomethylene) androstan 3,8 ol- 17-one [I; R is H, R is H, X is H; Y and Y are CH N=B is NHCH(CH can be prepared by replacing the piperidine in Example 1 by a molar equivalent amount of cycloheptylamine.

Example 7 1'6 (dicyclohexylaminomethylene) androstan 3 3 ol- 17-one [1; R is H, R is H, X is H Y and Y are CH N=B is N(C H can be prepared by replacing the piperidine in Example 1 by a molar equivalent amount of dicyclohexylamine.

Example 8 16 [(2 methyl 1 piperidyl)methylene]androstan- 3,8-ol-17-one [I; R is H, R is H, X is H Y and Y are CH N=B is Z-methyl-l-piperidyl] can be prepared by replacing the piperidine in Example 1 by a molar equivalent amount of Z-methylpiperidine.

Example 9 16 [(4 morpholinyl)methylene]androstan 3;? -oll7-one [1; R is H, R is H, X is H Y and Y are CH N=B is N (CH O] can be prepared by replacing the piperidine in Example 1 by a molar equivalent amount of morpholine.

Example 10 16 [N (cyclohexyl)methylaminomethylene]androstan-3fl-ol-l7-one [1; R is H, R is H, X is H Y and Y are CH N=B is N(C H )(CH3)] can be prepared by replacing the piperidine in Example 1 by a molar equivalent amount of N-(cyclohexyl)methylamine.

Example 11 16 [N (benzyl)methylaminomethylene]androstan- 3fl-ol-l7-one [1; R is H, R is H, X is H Y and Y are CH N=B is N(CH (CH C H can be prepared by replacing the piperidine in Example 1 by a molar equivalent amount of N-(benzyl)methylamine.

Example 12 16 [,8 (3,4 dimethoxyphenyl)ethylaminomethylene]androstan-3fi-ol-17-one [I; R is H, R is H, X is H Y and Y are CH N=B is HNCH CH C H (OCH 3,4] can be prepared by replacing the piperidine in Example 1 by a molar equivalent amount of 13-(3,4-dimeth oxyphenyl ethylamine.

Example 13 16 [B hydroxy )3 (4 hydroxyphenyl)ethylaminomethylene]androstan-3,8-ol-17-one [I; R is H, R is H, X is H Y and Y are CH N=B is HNCH CH OH C H OH-4] can be prepared by replacing the 1 by a molar equivalent droxyphenyl) ethylamine.

piperidine in Example amount of ,8-hydroxy-p-(4 h Example 14 Example 15 16 [2 (1 pyrrolidyl)ethylaminomethylene]androstan-3fl-ol-l7-one [1; R is H, R is H, X is H Y and Y are CH N=B is HNCH CH N(CH can be prepared by replacing the piperidine in Example 1 by a molar equivalent amount of 2-(1-pyrrolidyl)ethylamine.

Example 16 16 (di n butylaminomethylene)androstan 3e ol 17-one [1; R is H, R is H, X is H Y and Y are CH N:B is N(n-C H can be prepared by replacing the piperidine in Example 1 by a molar equivalent amount of di-n-butylamine.

Example 17 16 (dibenzylaminomethylene)androstan 35 o1 17 one [1; R is H, R is H, X is H Y and Y are CH N=B is N(C H CH can be prepared by replacing the piperidine in Example 1 by a molar equivalent amount of dibenzylamine.

Example 18 16 [(1 pyrrolidyl)methylene]etiocholan 3a ol 11,17-dione [1; R is H, R is H, X is O, Y and Y are CH N=B is N(CH was prepared from 4.00 g. of 16-hydroxymethyleneetiocholan-3a-ol-11,17-dione and 2.5 ml. of pyrrolidine in 150 ml. of benzene according to the manipulative procedure described above in Example 1. There was thus obtained 4.56 g. of product, M.P. 238- 241 C. (uncorr.), which when recrystallized from ethyl acetate and twice from benzene and dried at 130 C. in vacuo for eight hours gave 16-[(1-pyrrolidyl)methylene]- etiocholan-3a-ol-1l,17-dione in the form of pale yellow prisms, M.P. 2402-24-40 C. (dec.) (corr.),

(1% in chloroform); ultraviolet maximum at 328 mp (E=28,743).

Analysis.Calcd. for C H NO C, 74.76; H, 9.15'; N, 3.63. Found: C, 74.95; H, 9.11; N, 3.64.

Example 19 16 [(1 pyrrolidyl)methylene] 5 androsten 3 8 0l-17-one [II; R is H, R is H, X is H Y and Y are CH N=B is N(CH was prepared from 6.32 g. of 16-hydroxymethylene-5-androsten-3B-ol17-one and 4.0 g. of pyrrolidine in 150 ml. of benzene according to the manipulative procedure described above in Example 1. There was thus obtained 7.00 g. of product, M.P. 252 257 C. (uncorr.), which when recrystallized from absolute ethanol and dried at 100-110" C. in vacuo for eight hours gave 16-[(1-pyrrolidyl)methylene]-5-androsten-3B- ol-17-one in the form of pale yellow leaflets, M.P. 254.6- 259.2 (dec.) (corr.), [a] =1O5.9iO.4 (1% in chloroform); ultraviolet maximum at 328 m (E: 28,274).

Analysis.Calcd. for C H NO C, 78.00; H, 9.55; N, 3.79. Found: C, 77.80; H, 9.38; N, 3.80.

Example 20 16 [(1 pyrrolidyl)methylene] androstan 3B ol 17-one [1; R is H, R is H, X is H Y and Y are CH N=B is N(CH was prepared from 15.92 g. of 16- hydroxymethyleneandrostan-3p-ol-l7-one and 8.3 ml. of pyrrolidine in 750 ml. of benzene according to the manipulative procedure described above in Example 1. There was thus obtained 18.07 g. of product, M.P. 206- 208 C. (uncorr.), which when recrystallized from benzene and from ethyl acetate and dried at 130 C. in vacuo for eight hours gave 16-[(1-pyrrolidyl)methylene]- androstan-3B-ol-17-one in the form of pale yellow prisms, M.P. 206.6209.4 C. (corr.), [a] =36.7i0.3 1% in chloroform); ultraviolet maximum at 328 my. (E=28,5'50).

Analysis.-Calcd. for C H NO C, 77.57; H, 10.04; N, 3.77. Found: C, 77.44; H, 9.72; N, 3.72.

Example 21 16 (dimethylaminomethylene)androstan 3/3 ol 17 one [1; R is H, R is H, X is H Y and Y are CH N=B is N(CH A solution of 5.0 g. of 16-hydroxymethyleneandrostan- 3l3-ol-l7-one in 200 ml. of benzene was cooled to 10 C. Anhydrous dimethylamine (5.0 ml.) was added, and the mixture was stirred and allowed to warm at room temperature. The reaction mixture was slowly heated on a steam bath, refluxed for ten minutes and cooled with stirring, whereupon there separated 3.66 g. of product, M.P. 272-277 C. (uncorr.). The latter was collected and recrystallized from a methanol-ethyl acetate mixture and then from methanol alone, and dried at C. for twenty-four hours in vacuo over phosphorus pentoxide to give 16 (dimethylaminomethylene)androstan 3 8 ol 17-one, M.P. 275.6-283.2 C. (corr.),

(1% in chloroform); ultraviolet maximum at 319 m (E=16,800).

Analysis.-Calcd. for C H NO C, 76.47; H, 10.21; N, 4.05. Found: C, 76.26; H, 10.13; N, 3.98.

Example 22 16 (cyclohexylaminomethylene)androstan 33 ol 17-one [1; R is H, R is H, X is H Y and Y are CH N:B is NHCH(CH was prepared from 15.2 g. of 16-hydroxymethyleneandrostan-3 3-01-17-one and 9.52 g. of cyclohexylamine in 500 ml. of benzene according to the manpulative procedure described above in Example 1. The crude product was dissolved in benzene and chromatographed on a column of 700 g. of alumina. The column was eluted with benzene and then with benzene containing increasing quantities of ether. There was thus obtained 17.33 g. of product, M.P. 169-171 C. (uncorr.), which when recrystallized from ethanol gave 16-(cyclohexylaminomethylene androstan-3B-ol-17-one containing one molecule of ethanol of crystallization, M.P. indefinite, starting at 126.4 C., [a] =38.3 (1% in chloroform); ultraviolet maximum at 318 m (E=25,700).

Analysis.-Calcd. C26H41NO2.C2H5OH: C, H, 10.63; N, 3.14; O, 9.89. Found: C, 75.25; H, 10.50; N, 3.08; O, 9.77.

Example 23 16 [(2 diethylaminoethylamino)methylene]androstan-3B-ol-17-one [1; R is H, R is H, X is H Y and Y are CH N=B is NHCH CH N('C H was repared from 3.30 g. of 16-hydroxymethyleneandrostan-3fl-ol-17-one and 1.26 g. of Z-diethylaminoethylamine in 200 ml. of benzene according to the manipulative procedure described above in Example 1. The product was recrystallized successively from methanol, ethyl acetate and methanol and dried at 90 C. in vacuo to give 16-[(2-diethylaminoethylamino)methylene] androstan 3B ol 17- one, M.P. 173.0-176.8 C. (corr.), [a] =40.6i 0.5 1% in chloroform); ultraviolet maximum at 315 m (E=24,900).

Analysis.Calcd. for C H N O C, 74.95; H, 10.65; N, 6.72. Found: C, 75.25; H, 10.52; N, 6.60.

Example 24 16 [2 (4 morpholinyl)ethylaminomethylene]- androston-3fl-ol-l7-one [1; R is H, R is H, X is H Y and Y are CH N=B is NHCH CH N(CH O] was prepared from 3.30 g. of 16-hydroxymethyleneandrostan- 3,8-ol-17-one and 1.42 g. of 2-(4-morpholinyl)-ethylamine in 300 ml. of benzene according to the manipulative procedure described above in Example 1. There was thus obtained 3.19 g. of product, M.P. 163-178 C. (uncorr.), which was chromatographed on g. of alumina, eluted with ether-methanol (99:1), recrystallized three times from ethyl acetate and dried to give 16-[2-(4-m0rpholinyl) ethylaminomethylene] andros'tan-3fi-ol-17-one, M.P. 184.8187.8 'C. (corr.), [a] ==,34.8iO.1 (1% in chloroform); ultraviolet maximum at 314 me (E: 24,700).

Analysis.Calcd. for C H N O C, 72.52; H, 9.83; N, 6.51. Found: C, 72.60; H, 10.02; N, 6.45.

Example 25 16 [(1 hexamethylenirnino)methyleneiletiocholan- 3a-ol-l1,l7-dione [I; R is H, R is H, X is O, Y and Y are CH N=B is N(CH was prepared from 3.00 g. of 16 hydroxymethyleneetiocholan 3a ol 11,17- dione and 2.0 ml. of hexamethylenimine in 60 ml. of benzene according to the manipulative procedure described above in Example 1. The product was recrystallized from ethyl acetate and dried at 110 C. in vacuo for seven hours to give 16-[(l-hexamethylenimino)rnethylene]etiocholan-3a-ol-11,17-dione in the form of colorless needles, M.P. 193.2195.2 C. (corn), [a] =-|78.6 (1% in chloroform); ultraviolet maximum at 324 mp (E=29,200).

Analysis-Calcd. for C H NO C, 75.50; H, 9.51; N, 3.39. Found: C, 75.75; H, 9.76; N, 3.16.

Example 26 16 (N -methylcyclohexylaminomethylene) 5 androsten-3p-ol-17-one [II; R is H, R is H, X is H Y and Y' are CH N=B is N(CH (C H was prepared from 6.32 g. of 16-hydroxymethylene-5-androsten-3fi-ol- 17-one and 6.78 g. of N-methylcyclohexylamine in 300 ml. of benzene according to the manipulative procedure described above in Example 1. There was thus obtained 5.64 g. of 16-(N-methylcyclohexylaminomethylene)-5- androsten 3B ol 17 one, M.P. 222227 C. (dec.) (uncorr.).

Example 27 2,16 bis[(l -pyrrolidyl)methylene] 4 androstene- 3,17-dione [V; R is H, X is H Y and Y are CH N=B iS N A mixture of 3.0 g. of 2,16-bishydroxyrnethyl-4-androstene-3,17-dione, 1.5 g. of pyrrolidine and 600 ml. of henzene was refluxed for seventeen hours in a Bidwell- Sterling moisture trap apparatus to collect the water formed in the reaction. The reaction mixture was concentrated in vacuo, and the residue was triturated with ether, giving 3.67 g. of product, M.P. 250-258 C. (dec.) (uncorr.). Recrystallization of the latter from an ethyl acetate-methanol mixture and drying at 100 C. for five hours in vacuo gave 2,16-bis[( l-pyrrolidyl)methylene]-4 androstene-3,17-dione in the form of light yellow needles, M.P. 251.2262.8 C. (dec.) (corn), [a] =-245.3: 0.2 (1% in chloroform); ultraviolet maxima at 249, 331 and 373 m (E=18,200, 32,900 and 16,300).

' Analysis.-Calcd. for C H N O C, 77.62; H, 8.99; N, 6.25. Found: C, 77.50; H, 9.20; N, 6.22.

2,16 bis[(l -pyrrolidyl)methylene] 4 androstene- 3,17-dione reacts with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, tartaric acid, quinic acid, naphthalenesulfonic acid, methyl iodide, ethyl bromide, allyl bromide, benzyl chloride, or 2-chlorobenzyl chloride to give the hydrochloride, hydrobromide, sulfate (or bisulfate), phosphate (or acid phosphate), tartrate (or bitartrate), quinate, naphthalenesulfonate, methiodide, ethobromide, allobromide, benzochloride, or 2-chlorobenzochloride salts, respectively. If one molar equivalent of acid or ester is used with respect to the free base, a mono-acid-addition or mono-quaternary salt is obtained, whereas if two molar equivalents or more of acid or ester are used, a bis-acid-addition or bis-quaternary ammonium salt is obtained.

Example 28 2,16 bis[(l -piperidyl)methylene] 4 androstene- 3,17-dione [V; R is H, X is H Y and Y are CH N=B is N(CH can be prepared by replacing the pyrrolidine in Example 27 by a molar equivalent amount of piperidine.

Example 29 2,16 bis[(n hexyl)aminomethylene] 4 androstene-3,17-dione [V; R is H, X is H Y and Y are CH N=B is NH(CH CH can be prepared by replacing the pyrrolidine in Example 27 by a molar equivalent amount of n-hexylamine.

Example 30 2,16 bis(benzylaminomethylene) 4 -androstene- 3,17-dione [V; R is H, X is H Y and Y are CH N=B is NHCH C H can be prepared by replacing the pyrrolidine in Example 27 by a molar equivalent amount of benzylamine.

Example 31 2,16 bis(cyclopropylaminomethylene) 4 -androstene- 3,17-dione [V; R is H, X is H Y and Y are CH N=B is NHCH(CH can be prepared by replacing the pyrrolidine in Example 27 by a molar equivalent amount of cyclopropylamine.

Example 32 2,16 bis (cycloheptylaminomethylene) 4 andros'tene- 3,17-dione [V; R is H, X is H Y and Y are CH N=B is NHCH(CH can be prepared by replacing the pyrrolidine in Example 27 by a molar equivalent amount of cycloheptylamine.

Example 33 2,16 bis(dicyclohexylaminomethylene) 4 androstene-3,17-dione [V; R is H, X is H Y and Y' are CH N=B is N(C H can be prepared by replacing the pyrrolidine in Example 27 by a molar equivalent amount of dicyclohexylamine.

. Example 34 2,16 bis[(2 methyl 1 piperidyl)methylene] 4- androstene-3,17-dione [V; R is H, X is H Y and Y are CH N=B is 2-methyl-l-piperidyl] can be prepared by replacing the pyrrolidine in Example 27 by a molar equivalent amount of 2-methylpiperidine.

Example 35 2,16 bis(di n butylaminomethylene) 4 androstene3,17-dione [V; R is H, X is H Y and Y' are CH N=B is N(n-C.,H can be prepared by replacing the pyrrolidine in Example 27 by a molar equivalent amount of di-n-butylamine.

Example 36 2,16 bis(dibenzylaminornethylene) 4 androstene- 3,17-dione [V; R is H, X is H Y and Y are CH N=B is N(C H CH can be prepared by replacing the pyrrolidine in Example 27 by a molar equivalent amount of dibenzylamine.

Example 37 2,16 bis(dimethylaminomethylene) 4 androstene- 3,17-dione [V; R is H, X is H Y and Y are CH N=B is N(CH can be prepared by replacing the pyrrolidine in Example 27 by a molar equivalent amount of dimethylamine.

Example 38 2,16 bis(cyclohexylaminomethylene) 4 androstene- 3,17-dione [V; R is H, X is H Y and Y are CH N=B is NHCH(CH can be prepared by replacing the pyrrolidine in Example 27 by a molar equivalent amount of cyclohexylamine.

Example 39 2,16 bis[(2 diethylaminoethylamino)methylene]-4- androstene-3,17-dione [V; R is H, X is H Y and Y are CH N=B is NHCH CH N(C H can be prepared by replacing the pyrrolidine in Example 27 by a molar equivalent amount of Z-diethylaminoethylamine.

13 Example 41 2,16-bis[(1-hexamethylenimino)methylene] 4 androstene-3,17-dione [V; R is H, X is H Y and Y are CH N=B is N(CH can be prepared by replacing the pyrrolidine in Example 27 by a molar equivalent amount of hexamethylenimine.

Example 42 2,16-bis(aminomethylene) -4-androstene-3 ,17-dione [V; R is H, X is H Y and Y are CH N=B is NH can be prepared by treating a solution of 2,16-bis(hydroxymethylene)-4-androstene-3,17-dione in chloroform with dry ammonia gas at room temperature until saturated. After standing for several hours, the product is obtained by concentration of the solution.

Example 43' 2,16 bis[N (cyclohexyl)methylaminomethylene]-4- androstene-3,17-dione [V; R is H, X is H Y and Y are CH N=B is N(CH )(C H can be prepared by replacing the pyrrolidine in Example 27 by a molar equivalent amount of N-(cyclohexyDmethylamine.

Example 44 2,16-bis[ (4-morpholiny1 methylene] -4-androstene-3 ,17- dione [V; R is H, X is H Y and Y are CH N=B is N(CH O] can be prepared by replacing the pyrrolidine in Example 27 by a molar equivalent amount of morpholine.

Example 45 2,16-bis [N (benzyl)methylaminomethylene]-4-androstene-3,17-dione [V; R is H, X is H Y and Y are CH N=B is N(CH (CH C H)] can be prepared by replacing the pyrrolidine in Example 27 by a molar equivalent amount of N-(benzyl)methylamine.

Example 46 can be prepared by replacing the pyrrolidine in Example 27 by a molar equivalent amount of ,B-hydroxy-B-( lhydroxyphenyl ethylamine.

Example 48 16-[(l-piperidyl)rnethylene] 1,3,5() estratrien-3- ol-17-one UH; R is H, R is H, X is H Y. is CH N=B is N(CH can be prepared by replacing the 16-hydroxymethyleneandrostan-3B-ol-l7-one in Example 1 by a molar equivalent amount of 16-hydroxymethylene-1,3,5 (10)- estratrien-3-ol-17-one.

Example 49 16-[(l-piperidyDmethylene} 18 nor-1,3,5(10)-estratrien-3-o1-l7-one [III; R is H, R" is H, X is H Y is H, N=B is N(CH can be prepared by replacing the 16-hydroxymethyleneandrostan-3,6-01-17-one in Example 1 by a molar equivalent amount of 16-hydroxymethylenel8-nor-1 ,3,5(10)-estratrien-3-ol-17-one.

Example 50 16- (1 piperidyl)methylene] -1-methyl-1,3,5 10) -estratrien-3-0l-17-one can be prepared by replacing the 16- hydroxymethyleneandrostan-SB-ol-17-one in Example 1 by a molar equivalent amount of 16-hydroxymethylene- 1-methy1-1,3,5 (10)-estratrien-3-o1-17-one.

1 4 Example 51 16 [(1 piperidyl)methylene]-1,3,5(l0),6,8-estrapentaen-3-ol-17-one can be prepared by replacing the 16- hydroxymethyleneandrostan-3,B-ol-17-one in Example 1 by a molar equivalent amount of 16-hydroxymethylene- 1,3,5(10),6,8-estrapentaeu-3-ol-17-one.

Example 52 16- (1 piperidyl)methylene]-1,3,5(10) ,7-estratetraen- 3-o1-17-one can be prepared by replacing the 16-hydroxymethyleneandrostan-Iafi-ol-17-one in Example 1 by a molar equivalent amount of 16hydroxymethylene-1,3,5(10),7- estratetrae-n-3-ol-17-one.

Example 53 16 [(1 piperidyl)methylene]-l,3,5(10),6,8-estrapentaen-3,14-diol-17-one can be prepared by replacing the 16-hydroxymethyleneandrostau-Isfi-ol-17-0ne in Example 1 by a molar equivalent amount of 16-hydroxymethylene- 1,3,5(10),6,8-estrapentaen-3,14-diol-l7-one.

Example 54 16-[(1-piperidyl)me-thylene] 3 methoxy-1,3,5(10) estratrien-17-one [III; R is H, R is CH X is H Y is CH N=B is N(CH can be prepared by replacing the 16-hydroxymethy1eneandrostan-Sfi-ol-17-one in Example 1 by a molar equivalent amount of 16-hydroxymethylene-3-methoxy-1,3,5 10) -estratrien-l7-one.

Example 55 16 [(1 piperidyl)methylene]-1,3,5(10)-estratrien-3- ol-11,17-dione [III; R is H, R is H, X is O, Y is CH N=B is N(CH can be prepared by replacing the 16- hydroxymethyleneandrostan-3B-ol-17-0ne in Example 1 by a molar equivalent amount of 16-hydroxymethylene-1,3, 5( 10)-estratrien-3-ol-11,17-dione;

Example 56 l6-[1-(1-piperidyl)e-thylidene] 3 acetoxy-1,3,5(10)- estratrien-17-one [III; R is CH R is CH CO, X is H Y is CH N=B is N(CH can be prepared by replacing the 16-hydroxymethyleneandrostan-3B-ol-17-one in Example 1 by a molar equivalent amount of 3-acetoxy- 16-acetyl-1,3,5( 10) -estratrien-17-one.

Example 57 16-[(1-piperidyl)methylene] 5 androstene 112,35- diol-l7-one can be prepared by replacing the 16-hydroxymethyleneandrostan-3,B-ol-17-one in Example 1 by a molar equivalent amount of 16-hydroxyrnethylene-5- androstene-1a,3,8-dio117-one.

Example 58 16-[(1-piperidyl)methylene] 4 androstene 35,19- diol-17-one can be prepared by replacing the 16-hydroxymethyleneandrostan-Bfi ol 17 one in Example 1 by a molar equivalent amount of 16-hydroxymethylene-4- androstene-3 8,19-di0l-17-one.

Example 59 16-[(1-piperidyl)methylene] 3 ethoxy 3,5-androstadien-l7-one can be prepared by replacing the 16-hydroxymethyleneandrostan-3p-ol-l7-one in Example 1 by a molar equivalent amount of 16-hydroxymethylene-3- ethoxy-3,5-androstadien-17-one.

Example 60 16-[(l-piperidyDmethylene] 3 ethoxy 19- nor- 3,5-androstadien-17-one can be prepared byreplacing the 16-hydroxymethyleneandrostan-3B-ol-17-0ne in Example 1 by a molar equivalent amount of 16-hydroxymethylene-3-ethoxy-19-nor-3,5-androstadien-17-one.

Example 61 16-[(l-piperidyDmethylene] 3 ethoxy 3,5 androstadien-11B-ol-17-one canbe prepared by replacing the l6-hydroxymethyleneandrostan-Zip-0L17-one in Example 1 by a molar equivalent amount of 16-hydroxymethylene-3 -ethoxy-3,S-androstadien-1lB-ol-l7-one.

Example 62 16[(l-piperidyl)methylene] 4 androsten 11,8 ol- 3,17-dione [IX; R is H, X is (H) (OH), Y and Y are CH N=B is N(CH can be prepared by heating 16-[(1-piperidyl)rnethylene] 3 ethoxy 3,5 androstadien-1118-ol-l7-one with dilute acetic acid.

Example 63 16[(1-piperidyl)methylene] 3oz methylandrostan-BB- ol-l7-one can be prepared by replacing the 16-hydroxymethyleneandrostan-3fi-ol 17 one in Example 1 by a molar equivalent amount of l6-1ydroxymethylene 30cmethylandrostan-3fl-ol-17-one.

Example 64 16[(l-piperidyl)methylene]etiocholane 3a,12a diol- 17-one can be prepared by replacing the l6-hydroxymethyleneandrostan-3B-ol 17 one in Example 1 by a molar equivalent amount of l6-hydroxymethyleneetiocholane-3a,l2a-diol-l7-one.

Example 65 16-[(1-piperidyl)methylene] 3 mercapto 5 androsten-17-one can be prepared by replacing the l6-hydroxymethyleneandrostan-3fl-ol-17 one in Example 1 by a molar equivalent amount of 16-hydroxymethylene-3- mercapto-57 -androsten-17-one.

Example 66 16[(l-piperidyl)methylene] 5,7 androstadien 3- ol-17-one can be prepared by replacing the 16-hydroxymethyleneandrostan-3fi-ol l7 one in Example 1 by a molar equivalent amount of l6-hydroxymethylene-5,7- androstadien-3-ol-l7-one.

Example 67 16-[(l-piperidyl)methylene] 9,(11) etiocholen 3aol-l7-one can be prepared by replacing the 16-hydroxymethyleneandrostan-3B-ol-17-one in Example 1 by a molar equivalent amount of 16-hydroxymethylene9'( l1)- etiocholen-3a-ol-17-one.

Example 68 be caused to react with anhydrous hydrogen fluoride in chloroform solution to give 16- l-piperidyl) methylene] 9a-fluoroetiocholane-3 oc,l 1fi-diol-17-one.

Example 69 16-[(1-piperidyl)methylene] 4 androsten l7 one can be prepared by replacing the l6-hydroxymethyleneandrostan-3fl-ol-17-one in Example 1 by a molar equivalent amount of 16-hydroxymethylene-4-androsten-17-one.

Example 70 16-[(1-piperidyl)rnethylene]androstan 5- ol 17-one can be prepared by replacing the 16hydroxymethyleneandrostan-3/3-ol-l7-one in Example 1 by a molar equivalent amount of 16-hydroxymethyleneaudrostan-S-ol-l7- one.

Example 71 l6-[(l-piperidyl)-n-butylidene]androstan 3/3 ol 17- one [1; R is CH CH CH R is H, X is H Y and Y are CH N=B is N( C H can be prepared by replacing the l6-hydroxymethyleneandrostan 3B o1 l7 one in Example 1 by a molar equivalent amount of 16-butyrylandrostan-318-ol-17-one.

Example 72 l6-[(l-piperidyl)methylene] 4,4 dimethyl 5 androstene-3,l7-dione can be prepared by replacing the 16- hydroxymethyleneandrostan-3fi-ol-17-one in Example 1 by a molar equivalent amount of l6-hydroxymethylene- 4,4-dimethyl-5-androstene-3,l7 dione 3 monoethylene glycol ketal, and finally cleaving the ketal grouping by treating it with dilute acetic acid.

Example 73 16-[(1-piperidyl)methylene] 4 methyl 5 androstene 3,17 dione can be prepared by replacing the 16- hydroxymethyleneandrostan 36 ol l7 one in Example 1 by a molar equivalent amount of 16-hydroxymethylene-4-methyl-5-androstene 3,17 dione 3 monoethylene glycol ketal, and finally cleaving the ketal grouping by treating it with dilute acetic acid.

Example 74 16-[(1 piperidyl)methylene] 19 norandrostane- 3,17-dione [1; R is H, R is H, X is H Y is CH Y is H, N=B is N(CH can be prepared by replacing the 16-hydroxymethyleneandrostan-3,B-ol-l7 one in Example 1 by a molar equivalent amount of l6-hydroxymethylene 19 norandrostane 3,17 dione 3-monoethy1ene glycol ketal, and finally cleaving the ketal grouping by treating it with dilute acetic acid.

Example 75 2,l6-bis[l-(l pyrrolidyl)ethylidene] 4 androstene- 3,17-dione [V; R is CH X is H Y and Y are CH N=B is N(CH can be prepared by replacing the 2,16 bishydroxymethylene 4 androstene 3,17-dione in Example 27 by a molar equivalent amount of 2,16- diacetyl-4-androstene-3, 17-dione.

Example 76 2,16-bis[(1 pyrrolidyl)methylene] 6a methyl 4- androsten-l1fi-ol-3,17-dione can be prepared by replacing the 2,16 bishydroxymethylene-4-androstene 3,17 dione in Example 27 by a molar equivalent amount of 2,16-bishydroxymethylene-6a-methyl-4-androsten 11/3-ol 3,l7- dione.

Example 77 2,16 bis[(l pyrrolidyl)methylene] 4 androstene- 3,11,17-trione [V; R is H, X is O, Y and Y are CH N=B is N(CH can be prepared by replacing the 2,16-bishydr0xymethylene-4-androstene-3,l7-dione in Example 27 by a molar equivalent amount of 2,16-bishydroxymethylene-4-androstene-3, l 1,17-trione.

Example 78 2,16 bis[(1 pyrrolidyl)methylene] 6 fiuoro 4- androstene-3,l1,17-tri0ne can be prepared by replacing the 2,16-bishydroxymethylene-4-androstene-3,l7-dione in Example 27 by a molar equivalent amount of 2,l6@bishydroxymethylene-6-fluoro-4-androstene-3,l1,17-trione.

Example 79 2,16 bis l-pyrrolidyl) methylene] etiocholane-7 3, 14adiol-3,17-dione can be prepared by replacing the 2,16-bishydroxymethylene-4-androstene-3,17-dione in Example 27 by a molar equivalent amount of 2,16-bishydroxymethyleneetiocholane-718,14a-diol-3,17-dione.

Example 80 2,16 bis[(1 pyrrolidyl)methylene] 18,19 bisnor- 4-androstene-3,l7-dione [V; R is H, X is H Y and Y' are H, N=B is N(CH can be prepared by replacing the 2,16-bishydroxymethylene-4-androstene-3,17 dione in Example 27 by a molar equivalent amount of 2,16-bishydroxymethylene-18,l9-bisnor-4-androstene-3,17-dione.

17 Example 81 16 [(1 piperidyDmethylene] 3,5 cycloandrostan- 6-ol-17-one can be prepared by replacing the 16-hydroxymethyleneandrostan-3fi-ol-17-one in Example 1 by a molar equivalent amount of 16-hydroxymethylene-3,S-cycloandrostan-6-ol-17-one.

Example 82 16 [(1 piperidyl)methylene] -A -3,5-cycloandrostenl7-one can be prepared by replacing the 16-hydroxymethyleneandrostan-3fl-ol-17-one in Example 1 by a molar equivalent amount of 16-hydroxymethylene-A -3,5-cycloandrosten-l7-one.

Example 83 16 [(1 piperidyl)methylene] 20 methyl 4- androstene-3,17-dione can be prepared by reacting 20tmethy1-5-androstene-3,17-dione 3 -rnonoethylene glycol ketal (prepared by oxidizing 2ot-methyl-5-androsten-17,8- ol-3-one ethylene glycol ketal with chromic oxide in pyridine) with ethyl formate in the presence of sodium methoxide, and reacting the resulting l6-hydroxyrnethylene derivative with piperidine according to the, manipulative procedure described above in Example 1, followed by hydrolyzing the ketal group by heating with dilute acetic acid.

Example 84 16 [(1-piperidyl)methylene]-4 chloro-4-androstene- 3,17-dione can be prepared by reacting 4-chloro-4-androstene 3,17 dione 3 monoethylene glycol (prepared by oxidizing 4-chloro-5-androsten-17,8-01-3-0ne ethylene glycol ketal with chromic oxide in pyridine) with ethyl formate in the presence of sodium methoxide, and reacting the resulting lfi-hydroxymethylene derivative with piperidine according to the manipulative procedure described above in Example 1, followed by hydrolyzing the ketal group by heating with dilute acetic acid.

Example 85 16 [(1 piperidyl)methylene] 93,11 8 epoxy 4- androstene-3,17-dione can be prepared by reacting 95,11,8- epoXy-4-androstene 3,17-dione 3 monoethylene glycol ketal with ethyl formate in the presence of sodium methoxide, and reacting the resulting l6-hydroxymethylene derivative with piperidine according to the manipulative procedure described above in Example 1, followed by hydrolyzing the ketal group by heating with dilute acetic acid.

16 [(1 piperidyl)methylene] 913,115 epoxy 4- androstene-3,l7-dione can be caused to react with hydrofluoric acid, hydrochloric acid or hydrobromic acid to give, respectively, 9a-fiuoro-, 9a-chloroor 9a-bromo-16- l-piperidyl) methylene] 4-androsten-1 1,B-o1-3,17 dione. The latter can be oxidized with chromic oxide in pyridine solution to give the corresponding ll-oxo compounds.

I claim:

1. A l7-oxo-steroid having from seventeen to about twenty-three carbon atoms exclusive of ester radicals and being further substituted in the 16-position by the grouping =C(R)N=B wherein N=B is selected from the group consisting of primary amino, and basic secondary and tertiary amino having a molecular weight less than about 200, and R is selected from the group consisting of hydrogen and lower-alkyl.

2. A compound selected from the group consisting of (A) compounds having the formula wherein R represents a member of the group consisting of hydrogen and lower-alkyl; R represents a member of the group consisting of hydrogen and carboxylic acyl; X represents a member of the group consisting of H (H) (OH) and O; Y and Y represent members of the group consisting of hydrogen and methyl; and N=B is selected from the group consisting of primary amino, and basic secondary and tertiary amino having a molecular weight less than about 200; (B) acid-addition salts thereof; and (C) loweralkyl, lower-alkenyl and monocarbocyclic aryl-lower-alkyl quaternary ammonium salts thereof.

3. A compound according to claim 2 in which a double bond is present in the 5,6-position of the steroid nucleus.

4. 16-(di-lower-alkylaminomethylene)androstan-3p-ol- 17-one.

5. 16-(1-polymethyleniminomethylene)androstan 3,6- ol17-one, wherein the polymethylenimino group has. from 5 to 7 ring members.

6. A compound according to claim 5 in which a double bond is present in the 5,6-position.

7. 16 (1 polymethyleniminomethylene)etiocholan- 3a-ol-ll,l7-dione, wherein the polymethylenimino group has from 5 to 7 ring members.

8. l6 (di-lower-alkylamino-lower-alkylaminomethylene) -androstan-3,8-o1-17-one.

9. 16-[(1-piperidyl)methylene] androstan-3fl-ol-17-one.

10. l6-[(l pyrrolidyl)methylene]etiocholan 3a-ol- 11,1 7-dione.

11. 16-[(1 pyrrolidyl)methylene]-5-androsten-3B-ol 17-or1e.

12. 16-[(1 pyrrolidyl)methylene] androstan-3B-ol-l7- one.

13. 16-(dimethylaminomethylene)androstan 318-01-17- one.

14. 16-(cyclohexylaminomethylene)androstan 35-01- 17-one.

15. 16 [(2 diethylaminoethylamino)methylene]androstan-3/3-ol-17-one.

16. 16 -[2 (4 morpholinyl)ethylaminomethylene] androstan-3fi-ol-17-one.

17., 16 [(1 hexamethylenimino) methylene]etiocho- 12111-3cu01-1L17-dl0116.

18. A compound selected from the group consisting of (A) compounds having the formula wherein R represents a member of the group consisting of hydrogen and lower-alkyl; R represents a member of the group consisting of hydrogen, lower-alkyl and carboxylic acyl; X represents a member of the group consisting of H (H) (OH) and O; Y represents, a member of the group consisting of hydrogen and methyl; and N=B is selected from the group consisting of primary amino, and basic secondary and tertiary amino having a molecular weight less than about 200; (B) acid-addition salts thereof; and (C lower-alkyl, lowenalkenyl and monocarbocyclic aryl-lower-alkyl quaternary ammonium salts thereof.

19. A 3,17-dioxo-steroid having from seventeen to about twenty-one carbon atoms exclusive of ester radicals and being further substituted in both the 2- and 16- positions by the grouping =C(R)N=B wherein N=B is selected from the group consisting of primary amino, and basic secondary and tertiary amino having a molecular weight less than about 200, and R is selected from the group consisting of hydrogen and lower-alkyl.

20. A compound selected from the group consisting of (A) compounds having the formula wherein R represents a member of the group consisting of hydrogen and lower-alkyl; X represents a member of the group consisting of H (H) (OH) and O; Y and Y represent members of the group consisting of hydrogen and methyl; and N=B is selected from the group consisting of primary amino, and basic secondary and tertiary amino having a molecular Weight less than about 200; (B) acid-addition salts thereof; and (C) loWer-al'kyl, lower-alkenyl and monocarbocyclic aryl-lower-alkyl quaternary ammonium salts thereof.

21. A compound according to claim 20 in which a double bond is present in the 4,5-position of the steroid nucleus.

22. 2,16 bis(di-lower-alkylaminomethylene) 4 androstene-3,17-dione.

23. 2,16 bis(1-polymethylenirninomethylene) 4- androstene-3,17-dione, wherein the polymethylenimino group has from 5 to7 ring members.

24. 2,16 bis[( 1 pyrrolidyl)methylene]-4-androstene- 3,17-dione.

25. The process for preparing a 17-oxo-steroid having from seventeen to about twenty-three carbon atoms exclusive of ester radicals and being further substituted in the 16-position by the grouping =C(R)--N=B wherein wherein R represents a member of the group consisting of hydrogen and lower-alkyl; R represents a member of the group consisting of hydrogen and carboxylic acyl; X represents a member of the group consisting of H (H) (OH) and O; Y and Y represent members of the group consisting of hydrogen and methyl; and N=B is selected from the group consisting of primary amino, and basic secondary and tertiary amino having a molecular weight less than about 200, which comprises reacting a compound having the formula with a compound of the formula HN=B.

27. The process according to claim 26 in which a double bond is present in the 5,6-position of the steroid nucleus.

28. The process for preparing a 3,17-dioxo-steroid having from seventeen to about twenty-one carbon atoms exclusive of ester radicals and being further substituted in both the 2-and l6-positions by the grouping =C(R)N=B wherein N=B is selected from the group consisting of primary amino, and basic secondary and tertiary amino having a molecular weight less than about 200, and R is selected from hydrogen and lower-alkyl, which comprises reacting a 3,17-dioxo-steroid, having from seventeen to about twenty-three carbon atoms exclusive of ester radicals and being further substituted in both the 2- and 16-positions by the grouping with a compound of the formula HN=B.

29. The process for preparing a compound having the wherein R represents a member of the group consisting of hydrogen and lower-alkyl; X represents a member of the group consisting of H2, (H) (OH) and O; Y and Y represent members of the group consisting of hydrogen and methyl; and N=B is selected from the group consisting of primary amino, and basic secondary and tertiary amino having a molecular weight less than about 200, which comprises reacting a compound having the with a compound of the formula HN=B.

30. The process according to claim 29 in which a double bond is present in the 4,5-position of the steroid nucleus.

No references cited. 

1. A 17-OXO-STEROID HAVING FROM SEVENTEEN TO ABOUT TWENTY-THREE CARBON ATOMS EXCLUSIVE OF ESTER RADICALS AND BEING FURTHER SUBSTITUTED IN THE 16-POSITION BY THE GROUPING =C(R)-N=B WHEREIN N=B IS SELECTED FROM THE GROUP CONSISTING OF PRIMARY AMINO, AND BASIC SECONDARY AND TERTIARY AMINO HAVING A MOLECULAR WEIGHT LESS THAN ABOUT 200, R IS SELECTED FROM THE GROUP CONSISTING OF HYDROGEN AND LOWER-ALKYL. 